The myocardial failure associated with the late stages of bacterial septicemia is a major factor in the high mortality rate of patients suffering from bacterial infections. The cause of this myocardial failure is as yet unknown. The proposed studies will investigate the possibility that a failure of cardiac metabolism induced by alterations in substrate availability or by other blood-borne factors may be major determinants of cardiac contractile failure. To explore this problem studies will be initiated to first examine the time course of the hemodynamic (cardiac output, left ventricular stroke work and blood pressure) and blood metabolite changes (fatty acids, glucose, ketones, lactate) in the same animals. This will allow correlation of substrate availability with the time course of changes in myocardial function. Intracellular metabolite assays of hearts frozen during different phases of the septic course will reveal any differences in high energy phosphate levels and endogenous substrates stores from control animals fasted for equivalent times (since septic animals do not eat). This information will also serve as a basis for determing times during the septic course at which hearts will be isolated and perfused as a working heart preparation for study of persisting metabolic and functional defects determined from measurements of substrate oxidation and energy blance and from evaluation of myocardial function through construction of ventricular function curves. This will be done in the presence of adequate substrate and oxygen. To examine the mechanisms by which endotoxin and blood-borne factors depress cardiac function normal hearts will be perfused with plasma fractions isolated from fasted animals and from animals in low output and high output phases of sepsis. These hearts will also be evaluated for their metabolic capacity to produce high energy phosphates and to maintain adequate ventricular function. These studies will enable assessment of the adequacy of metabolic pathways to produce energy for the support of myocardial function.